Hypoglycemia is the major obstacle preventing the benefits associated with intensive insulin therapy. Low glucose levels can lead to cognitive impairment and even brain damage. Roles for brain glycogen have been suggested for both memory formation and protection against hypoglycemia-induced neuronal damage. The overall objective of this proposal is to determine the importance of brain glycogen in cognitive function and neuroprotection under hypoglycemic conditions. The PI will utilize genetically engineered mice with deficient brain glycogen stores to address the following aims: Aim 1. Does reduced brain glycogen impair cognitive function during hypoglycemia? The hypothesis is that if brain glycogen is important for protecting against hypoglycemia-induced impairment of cognitive function, learning ability will be impaired by hypoglycemia more in mice with reduced brain glycogen stores than in wild type control animals. Aim 2. Does brain glycogen provide protection against hypoglycemia-induced neuronal cell death? The hypothesis is that if brain glycogen is neuroprotective, hypoglycemia-induced neuronal cell death will be greater in mice deficient for brain glycogen than in wild type littermates. These would be the first studies where brain glycogen levels are intentionally manipulated in the whole animal by genetic modification. Should manipulation of brain glycogen levels prove beneficial, a small molecule regulator of glycogen metabolism in brain could perhaps be a useful therapeutic. PUBLIC HEALTH RELEVANCE: Low glucose in the blood, hypoglycemia, is the major obstacle preventing the benefits associated with intensive insulin therapy in patients with diabetes. This hypoglycemia can lead to cognitive impairment and even brain damage. The goal of these studies is to understand mechanisms that protect the brain from these deleterious effects during hypoglycemia.